A podcast of the interview is available here. A transcript of the interview appears below.

SB: This is Autism Research Connections #1. This is Seth Bittker, and our guest today is Dr. Richard Frye. Dr. Frye is Director of Autism Research, Director of the Autism Multispecialty Clinic, Co-Director of the Neurometabolic Clinic, Associate Professor of Pediatrics of Child and Behavioral Neurology at Arkansas Children’s Hospital Research Institute as well as University of Arkansas Medical School. Dr. Frye has written extensively on mitochondrial dysfunction in autism, autoimmunity of the folate receptor in autism, methylcobalamin and folinic acid in autism, the microbiome, as well as numerous other papers on autism. Dr. Frye, thank you for being with us today.

RF: Sure it is my pleasure.

SB: Dr. Frye I wonder if you could introduce us to what is mitochondrial dysfunction?

RF: Well we should start out with what is the mitochondria. So our cells which make up our body have different pieces in them that do different functions, and the mitochondria is the part of the cell that is best known for making all the energy in the cell, and it is a very unique part of the cell. First of all you don’t just have one mitochondria for every cell. You can have anywhere from hundreds to tens of thousands per cell in any cell in your body depending on how much energy that cell needs, and what we have found out that sometimes this powerhouse is not working the way it should. And so you can imagine if you are living in a city and the power and you have a blackout, there are so many things that are going to happen, and things won’t work. What we find is that mitochondrial problems or what we call mitochondrial dysfunction seems to be pretty prevalent in autism. Now the idea that the mitochondria doesn’t work and diseases associated with the mitochondria really are pretty new on the playing field of medicine. Really the first well known or well characterized disorders are really just in the 1980s that described diseases of mitochondrial disease, and for a long time we believed mitochondrial disease occurred when the mitochondria was very dysfunctional, that is just like if you were living in a city and there was a blackout and you had absolutely no power. So many of the early mitochondrial diseases were described where the mitochondria was not working at all. So the cells were not working in the body and the body became sick and many of the organs did not work, but what we are starting to find out and we think we see this in autism is that sometimes this powerhouse of the cell, the mitochondria, it’s not that it doesn’t work at all, but it doesn’t work up to the potential that is needed for the body to work optimally. So you can think of this as if you are kind of in the city you have a brown out where the power goes down a bit, maybe you can’t use your air conditioner, but the lights are still on. And what we find is that this is analogous to what we see in many children with autism is that this powerhouse of the cell isn’t working up to the capacity that is needed, and this is very important during development – during that time at which we see the onset of autism because the body is growing. When the body is growing, it needs lots of energy to grow. It needs lots of building blocks, and if it doesn’t have the resources that it needs, it is going to stall, and we believe that is what happens is that brain development stalls and doesn’t complete through the steps that it needs to fully develop and we end up with the characteristics of autism. So that is just in a nutshell you know mitochondria and why we think they are important in autism.

SB: That is a wonderful – or very revealing picture there that you have sketched for us. So when you suspect mitochondrial dysfunction what are the lab tests that you would typically order?

RF: Well it varies, and one of the problems that we have with mitochondrial disease and dysfunction again is it’s really the new player on the block. So the method for diagnosing it is still not all that well developed. So usually what we do is some of the standard labs which would be fasting labs first thing in the morning before breakfast where we look at biomarkers such as lactate or pyruvate. We also look at amino acids and their levels in the body because many times if the mitochondria is not working there will be certain patterns of amino acid abnormalities. We also look at fatty acid metabolism because fatty acids are also processed and burned by the mitochondria for fuel, and we look at many of these tests and we kind of put them together to see if there is a sign of mitochondrial dysfunction, and then if there is there are many other tests that really have to be done to confirm whether mitochondrial dysfunction is there or not, what is causing it, and to what extent it might be interfering with the life of the child.

SB: That is very well said. So if you find mitochondrial dysfunction, it seems like you might provide maybe carnitine. Are there other supplements you would consider providing or how do you treat it? How do you typically think about treating it?

RF: Sure. So every child is different and different doctors that treat mitochondrial disease treat them slightly differently. A child with autism and mitochondrial dysfunction is unique in many ways. First of all we know that many children with autism also have what we call redox abnormalities. That is the system that balances oxidative stress – that is toxic radicals in the body – isn’t working as well as it should be in many children with autism. We know that when the mitochondria is not working the same thing happens. We have this elevated level of oxidative stress. So one of the first things that we do is try to improve the body’s ability to make the antioxidant glutathione by giving B12 and folinic acid to help the systems that naturally make the natural antioxidants of the body – most notably glutathione.

The next thing we do to treat mitochondrial dysfunction that I find is very useful is something called CoQ10, and many people see CoQ10 for heart health – for general health as a vitamin that they can take, and CoQ10 is known as an antioxidant – is advertised as an antioxidant, but what a lot of people don’t know is that CoQ10 is actually part of the machinery of the mitochondria. That is the final common pathway of the mitochondria that make energy called the electron transport chain – the different parts of that chain – the so called complexes – actually transfer some of their energy using CoQ10. So CoQ10 is almost like the wires that connects some of the parts of the electron transport chain. When there is high levels of oxidative stress, it is used as an antioxidant and can be used up, and therefore it is not available to the mitochondria for the mitochondria to function. So that tends to be my second thing is to use CoQ10 which can act as both an antioxidant and help the mitochondria work. Other treatments as you noted are carnitine is extremely useful. Carnitine is important for fatty acid metabolism. It is also important for actually removing toxic organic acids from the body and cells and eliminating them from the body. So carnitine is definitely one of the go to vitamins. Also many of the B-vitamins are very important. So we supplement B-vitamins.

Another important supplement would be creatine. Creatine is creatine monohydrate which a lot of the body builders use. They use it because what it does is it creates phosphocreatine in the muscles which store energy. So when the mitochondria isn’t working, what it can do is it can actually store some of this energy and you store your energy in phosphocreatine. So creatine can go into the cells and particularly the muscles and actually store energy and so it can compensate for certain mitochondrial dysfunction.

The other thing that we find really is helpful for a lot of children with mitochondrial dysfunction is high doses of folinic acid because as you had mentioned in the beginning one of the things we do a lot of research on and have done clinical trials is central folate deficiencies – that is deficiencies in folate that seem to affect the brain but not the body, and central folate deficiencies are very important because of course folate is one of the essential vitamins. It is important for many of the essential functions of the cell. It ends up that your brain is protected by the blood brain barrier, and in order for many things to get across this blood brain barrier they need a special carrier to take them, and we find that this carrier that carries folate into the brain sometimes can be dysfunctional. We find that there are these folate autoantibodies that many children with autism have that block the ability of this carrier to work, but we also know this carrier needs lots of energy, and any part of the body that needs lots of energy is going to be affected if the mitochondria is not working. And so we find that many children have problems with cerebral folate deficiency or insufficiency and respond to high dose folinic acid. So in a nutshell those are some of the treatments that we usually start out and use for children with mitochondrial disorders or mitochondrial dysfunction.

SB: Thank you for sketching that out, and I believe I recall that you have done some – I believe it was a double blinded trial with folinic – is that accurate or not the case?

RF: Yes. That is definitely accurate. You know our first study was an open label study that was actually a large case series that I did with Dr. Rossignol where we showed that kids with the folate autoantibody seemed to respond very well to high doses of folinic acid with particularly increases in language. So we followed that up recently – we completed a double-blinded placebo controlled study where half the children are getting placebo, half getting folinic acid and neither their doctors nor the patients know, and what we actually showed in that trial is that the kids that got folinic acid had over a three month period – demonstrated a very significant increase in language as compared to the placebo. We also did some analysis to look to see if those kids that responded had the folate autoantibody and we found that those kiddos with autism and the folate autoantibody had a particularly large response to folinic acid. So we think that not only is it an important treatment just in general for children with autism but particularly those that have this autoantibody that block the ability of folate to cross the blood brain barrier.

SB: Congratulations on that work. I’m curious about the choice of folinic versus methylfolate or some other form of folate. Do you have any thoughts on whether folinic is maybe best in some sense for a larger number of children or whether there are other forms that would be useful?

RF: So theoretically the reason why we do folinic acid is that it’s a reduced form of folate. So one of the major health advances we have made in the United States and other developed countries is fortifying our food with folic acid but one thing a lot of people don’t realize about folic acid is that folic acid is the oxidized form of folate and because it is the oxidized form it’s not readily available for your body to use. So your body actually has to go through a number of steps to make it activated and reduce it and we know that some people particularly people with autism have a problem with the enzyme that actually reduces it. So many times just taking folic acid will not be sufficient especially in those that have certain polymorphism in genes that are responsible for reducing folic acid. So folinic acid is a reduced form of folate. So it more readily goes into the biochemical pathways that are important for the body and it’s readily used by the body. The block that we talked about in this transporter can be circumvented by using another transporter that transports folate into the brain and it’s called the reduced folate carrier and that carrier only can transport reduced folates. It can’t transport oxidized folates. So we use a form of reduced folate – that is folinic acid. And we use it at high doses for a number of reasons. One because the reduced folate carrier has a lower affinity for folate than the folate receptor alpha which is the one that is blocked. So you need higher doses because of decreased affinity, and in addition the levels of folate in the brain are actually higher than the levels in the blood. So that is why the folate receptor alpha –the one that is blocked – is so important under normal circumstances and why it takes energy because it actually transports folate from a lower concentration in the blood to a higher concentration in the brain. The reduced folate carrier is not so good at doing that. So you have to get higher levels of folate in the blood – reduced folates in the blood for it to get into the brain at adequate levels. So why do we folinic acid or also known as leucovorin calcium? So there are a number of reasons. The most important one is that the studies that have looked at this disorder of problems with central folate have used folinic acid and they have actually measured the levels of folate in the brain before and after folinic acid treatment. So we know that folinic acid works and we also know the approximate doses that it takes for it to work. So that is important. Now theoretically other reduced folates should work also. So other methylfolates and such should work but we are not so confident about what the doses are that need to be used. So if you use another type of reduced folate and it works you know that might be great, but if things aren’t working out the way that you want, you are kind of lost as far as knowing if your dosing is wrong or something else is not correct. So personally I like to stay with something that I know more about. The other thing about folinic acid also known as leucovorin calcium is that it has been used in oncology as rescue therapy to reduce side effects from many chemotherapy agents. So we know the safety profile of it also. In general folates are safe, but it gives you a little more confidence when you know that a compound has been used for many decades and people have had experience with it and there is no major side effects from it.

SB: Wow. Thank you for that explanation. So earlier we had spoken a little bit about mitochondrial dysfunction. We also have the autoimmunity of the cerebral folate receptor. When you are seeing these thing, do you have any hypothesis on is there an order in which this happens? So in other words, do you think that you initially have some sort of mitochondrial dysfunction, then that leads to the autoimmunity or is it the autoimmunity that then leads to mitochondrial dysfunction?

RF: It is really a great question. It is one thing that we are finding out is that a lot of kids with signs of autoimmunity with autoantibodies – not only the folate receptor autoantibodies – but other autoantibodies to the brain seem to also have mitochondrial dysfunction. For some reason they seem to go hand in hand, and it is not exactly clear why that is, or which came first – you know which was the chicken or which was the egg? And I think it is an important connection. We see that the two seem to go together. It maybe that it starts out with one or the other and it creates a viscous spiral that worsens both of them. So for example we know that the immune system and immune cells take a tremendous amount of energy to work. So if you have mitochondrial dysfunction, the immune cells aren’t going to be working up to their capacity, and they can end up becoming dysfunctional and creating autoantibodies. So those autoantibodies cause inflammation which will then cause oxidative stress and more mitochondrial dysfunction. So it can be a viscous spiral.

In the same way it may be an immune trigger. It may be that you have a slightly weak mitochondria and some type of inflammatory event happens which just pushes things over the edge where the mitochondria can’t handle it and they become dysfunctional. We are not sure, and it may be that there are many ways to get to the same place, and that is something that really future research has to look. You know I don’t want to [inaudible].

SB: Very interesting. Very interesting. So if you also have the microbiome coming into play –and I know you have written extensively on this as well – do you see that as further something that is downstream, upstream, or again we are not really sure how exactly the order works but it something that becomes dysfunctional?

RF: Yeah. The microbiome is just really fascinating, and the research that is coming out on the microbiome is extremely fascinating. We know that the microbiome especially early on in life – in the first three years of life – but probably in the first month – there are critical times when the microbiome is developing and influencing the immune system and the metabolic systems. We know that it helps program the immune system. We know that it can also interfere with metabolic systems also. You know there are some compelling studies that suggest that these changes in the microbiome seem to precede the onset of autism sometime suggesting that there is potentially some causative effects of the microbiome, although you can’t rule out that it is an epiphenomenon to something else. But there is lots of data that suggests that the microbiome has some type of real key relationship to the development of autism. You know the fact that children with autism tend to have more antibiotic use early on, which can change the microbiome. They tend to have other changes in diet – GI problems – that may precede the onset of autism. So I think it is really interesting, and I’m very interested to see what we find out in the near future. You know there are great studies now that are coming out not so much on autism but in other childhood diseases that show that really modifying the microbiome particularly within in the first month of life is preventative of many particularly immune diseases and allergic diseases. So there is a lot of data that seems to be pointing that this is really an important component and something that has really been underappreciated for a long period of time, and given the fact that it can modulate metabolic systems and can modulate the immune system, I think it is most likely a very important component to the etiology of autism, and so hopefully studies within the next five – ten years will give us those answers and will help us understand how we can change our lifestyles and our diets and such to manipulate the microbiome to make us healthier.

SB: Very interesting. Very interesting. So I know that in autism research recently there has been a big focus on biomarkers for autism and some of the work has gone into things like eye tracking and such. Do you have any candidate biomarkers you would be willing to tell us about?

RF: Yeah. I mean we work on more metabolic biomarkers – things like the folate receptor alpha. We find that many parent and particularly mothers of children with autism that have the folate autoantibody, their mothers also have it too. We know the same thing with many of the changes in redox metabolism that we see in children with autism, we also see them in moms. Right now we are also developing some markers of mitochondrial function and dysfunction that seems to be very unique to autism. We are developing those to help us not only understand how mitochondria are working or not working, but also our goal is to be able to use these tests early on in life and even prenatally to initiate treatment before autism onset occurs.

SB: That is brilliant – a great future. So I know earlier you had spoken about some of the over-the-counter therapeutics that you sometimes use. Are there any other over-the-counter therapeutics that you feel are just underutilized in autism that you would like to mention to our audience?

RF: Yeah. I think there is a lot of potential for a lot of different over-the-counter and other types of treatments. The issue with a lot of them is that they really haven’t been studied in well-controlled studies to actually tell us how helpful they would be, but we know for example one of the things that has gone through some double-blinded placebo controlled studies and seems to be very helpful for irritability is n-acetyl-cysteine which helps deplete[d] glutathione and decrease glutamate, the major excitatory neurotransmitter and something that can be purchased from suppliers and can be very helpful. As you mentioned carnitine. One of the other things that I use a lot of times is the Autism Nutritional Research Center’s multivitamin that Jim Adams put together, which he is showing two double-blinded placebo controlled studies to be helpful. Of course you know it is important when we talk about over-the-counter supplements that people understand that it is very important to get these supplements from reputable laboratories and producers as they can vary in quality quite a bit. It is just very important that you get good quality supplements, because if they don’t work you don’t know if it is because the supplement was poor quality and if you have a poor quality supplement , it can have things in it that you didn’t expect and that is not always good. So I think there is a lot of potential for certain over-the-counter supplements that can be useful. I think every child is different, and it is important to understand that there is not one size fits all. So I really encourage parents to see a physician that is knowledgeable in the use of both over-the-counter and non-over-the-counter treatments to see what would be best for a child, and really not do things so much themselves, but make sure that they have an experienced [physician] that guides them.

SB: That makes a lot of sense. You mentioned also about the importance of using trustworthy sources. Are there a couple of brands or names in the industry that you feel are unusually trustworthy with respect to the contents of their supplements?

RF: Yeah. There are certain laboratories – of course the USP seal is an independent laboratory that tests supplements that can verify what is in the supplements is good, but there [are] other different pharmacies and suppliers that I think are high quality. So I think that it is important for parents to talk to their support groups – other parents – to see what their experience is.

SB: Excellent. Also you mentioned the potential importance of prescription pharmaceuticals in the treatment of autism. What are some of the prescription pharmaceuticals that in your view are just underutilized in autism treatment?

RF: Yeah. I mean I think that many of the prescription pharmaceuticals still need to really be tested on kids with autism a little bit better. I think one of the problems is that really the only big studies that have been done have been done with antipsychotics which have significant side effects that should not be ignored. So personally when I see a patient I try to find out what symptoms are the key symptoms to treat and then direct treatment toward that whether it be prescription or non-prescription. I tend to try to avoid antipsychotic medications, but the studies on other prescription medications are very variable, and so I would say that it is important for anybody to see a doctor with knowledge of what has been really researched – what hasn’t been – what the best evidence is so that they get the best care for their child. And there are a variety of different medicines that can help, and I think that it needs to be kind of customized on a case by case basis.

SB: Makes total sense. Dr. Frye there is a lot of great autism research going on. Is there any recently that you have thought my goodness, this is really interesting, it is something we should be watching?

RF: Oh I think there is a lot. I think as you mentioned the microbiome research is incredible. I think there is a lot of really great research on the immune system. We are really finding out how the immune system and many autoantibodies seem to play into possibly not only causing autism but increasing the disability and symptoms in children of autism. I think those are two really important areas. Of course I am very excited about the research we have going on on metabolic systems. I’ll tell you what I like about metabolic systems, and why I think it is so important to research and look at is that these are systems that we can change. Although you know it’s exciting to look at the immune system, the immune system does not have any really great therapies that are extremely safe. So until we find really good therapies, I think there is going to be limitations to what we can do to modulate the immune system. Whereas things like the metabolic systems and the microbiome are two things that we can change pretty easily and safely and maybe have a big impact.

SB: That sounds very exciting. With respect to the metabolic system research that you are doing – obviously don’t tell us anything you don’t want us to know – but do you feel comfortable telling us anything about that research in terms of what you are doing – what you are looking at?

RF: Well what we are looking at is how these systems may be dysfunctional and why they are and what can be done about it and what type of things can be done to support them. What we are finding as I mentioned previously is that mitochondrial dysfunction seems to be very much linked with oxidative stress and immune dysfunction, and we are starting to learn how these are all connected and what things we can do to actually either alter these systems to normalize them or to make sure that they are working optimally so that the child and the body can work optimally.

SB: Sound great. Dr. Frye is there anything else that you would like us to know in terms of things we should be keeping an eye on with respect to autism research?

RF: Well I think that it is very important that we focus – I think as you mentioned before that really I think the focus so far for a lot of research has not been on treatment. I think there is a lot of treatment on the horizon – either novel treatments that we haven’t used yet or treatments that we believe that work that just have to be tested to make sure that we know how to use them. I think that understanding what is causing autism and how metabolic and immune systems are dysfunctional are very important areas of research that we have to concentrate on, and of course really the missing piece I think is that we have not been concentrating on how environmental influences may be triggering systems to go awry and cause autism through the microbiome or other systems and what we can do to prevent that from occurring.

SB: Brilliant. It makes a lot of sense. So Dr. Frye, thank you so much for being with us. This has been a truly illuminating conversation.

Hi Audrey,
I can see from this clinical trial (https://clinicaltrials.gov/ct2/show/NCT01602016) that Dr. Frye was working on that in the trial for folinic he would start at doses of .5 mg per kg and work up to doses of 2 mg per kg. Dr. Frye is a wonderful guy and he knows way more about this than I do, but these are very large doses, and if you are tempted to do something like this, I would start at much smaller doses.